Inhibition of matrix metalloproteinases (MMPs) as an approach to treat diseases such as cancer, arthritis, restenosis or multiple sclerosis is now an area of intense interest within the pharmaceutical industry (see Whittaker, M., Floyd, C. D.; Brown, P.; Gearing, A. J. H. Chem. Rev. 1999, 99, 2735-2776).
MMPs are a family of zinc-containing calcium dependent enzymes, including stromelysins, collagenases and gelatinases. Over twenty MMPs have been identified. MMPs are capable of degrading and remodeling many proteinaceous components of the extracellular matrix in both physiological and pathological conditions. Misregulation and overexpression of MMPs is believed to be a major factor in a number of disease states, most of them characterized by unwanted degradation of connective tissue. These include rheumatoid arthritis, tumor invasion, metastasis, angiogenesis, multiple sclerosis, periodontal disease, coronary artery disease, restenosis, congestive heart failure, abnormal wound healing, bone matrix degradation, osteoporosis, liver cirrhosis, cerebral ischemia, meningitis and others. Tumor cell invasiveness has been shown to be MMP-dependent, and MMP inhibitors have been shown to prevent tumor cell invasion in vitro and in vivo.
Coronary atherosclerosis and its clinical progression continue to be the leading cause of mortality in the Western society. Percutaneous transluminal coronary angioplasty (PTCA) has become a mainstay in the treatment of ischemic heart disease with an estimated over 1 million procedures performed annually in the US and Europe. PTCA procedures include balloon dilation, excisional atheroctomy, endoluminal stenting and laser ablation. Despite significant advances in reducing the acute complications of percutaneous revascularization procedures with pre-medications and better techniques, chronic restenosis of dilated lesions remains a serious and frequent problem, occurring in 20% to 30% of patients.
Some carbamoylphosphonate derivatives were described in WO 01/26661 as capable of inhibiting MMPs.